Copy number-independent allelic imbalance in mRNA is selected in cancer and has prognostic relevance

Allelic imbalance (AI) in levels of mRNAs in cancer is widely appreciated to result from somatic copy number alterations (CNA) affecting one allele. Apart from CNA, other mechanisms could lead to imbalanced mRNA expression of the alleles, and similarly drive cancer evolution by epistatic interactions with the somatic mutations. By integrating genomic and transcriptomic pan-cancer data, we show that mRNA allelic imbalance favoring the mutant allele in driver genes is subject to positive selection, generating second-hit events often independently of somatic CNA. In some cases, the somatic coding mutations could induce allele-specific expression directly, e.g. with splicing-altering exonic mutations, which can be selected in various cancer genes. However, in the majority of cases, these and related somatic mutation effects (which might in principle alter transcription output via impacting promoters or intragenic enhancers) do not explain the CNA-independent mRNA-level AI, suggesting prevalent epigenetic alterations affecting alleles differently in tumors. Importantly, the mRNA AI events associate with worse overall survival across all cancer types, outperforming various other predictive markers. Our study suggests that mRNA allelic imbalances can occur independently of CNA but similarly function as second-hit events to somatic mutations, driving tumorigenesis, and so represent valuable prognostic biomarkers for cancer patient stratification.